Xu Jinghui, He Xiaofei, Li Lili, Zhang Liying, Li Mingyue, Mu Yating, Yang Xiaofeng, Li Shiyin, Feng Yifeng, Zuo Zejie, Xu Yunqi, Hu Xiquan, Zheng Haiqing
Department of Rehabilitation Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
NPJ Parkinsons Dis. 2025 Mar 23;11(1):55. doi: 10.1038/s41531-025-00912-5.
Microglia are more susceptible to ferroptosis compared to neurons and astrocytes, which may compromise their phagocytic and clearance capabilities of α-synuclein (α-syn) in Parkinson's disease (PD). While the beneficial effects of physical exercise (PE) on reducing α-syn deposition in PD have been highlighted, the role of PE in modulating microglial ferroptosis remains unclear. This study focuses on the impact of exercise on inhibiting microglial ferroptosis and mitigating α-syn accumulation. We demonstrate that voluntary exercise effectively inhibits microglial ferroptosis. Mechanistically, PE-induced upregulation of SLC7A11 inhibits microglial ferroptosis by suppressing ALOX12, thereby enhancing microglial phagocytosis and clearance of α-syn, which is paralleled by improvements in neurological function in PD mice. Collectively, these findings not only underscore the critical role of microglial ferroptosis in the pathological progression of PD but also elucidate the molecular mechanism by which PE attenuates microglial ferroptosis via the SLC7A11/ALOX12 axis.
与神经元和星形胶质细胞相比，小胶质细胞更容易发生铁死亡，这可能会损害它们在帕金森病（PD）中对α-突触核蛋白（α-syn）的吞噬和清除能力。虽然体育锻炼（PE）对减少PD中α-syn沉积的有益作用已得到强调，但PE在调节小胶质细胞铁死亡中的作用仍不清楚。本研究聚焦于运动对抑制小胶质细胞铁死亡和减轻α-syn积累的影响。我们证明，自愿运动能有效抑制小胶质细胞铁死亡。机制上，PE诱导的SLC7A11上调通过抑制ALOX12来抑制小胶质细胞铁死亡，从而增强小胶质细胞对α-syn的吞噬和清除，这与PD小鼠神经功能的改善相平行。总的来说，这些发现不仅强调了小胶质细胞铁死亡在PD病理进展中的关键作用，还阐明了PE通过SLC7A11/ALOX12轴减轻小胶质细胞铁死亡的分子机制。
